Compositions comprising a phosphorus derivative of nicotinamide riboside and methods for modulation of nicotinamide adenine dinucleotide

ABSTRACT

The invention relates to compounds and compositions for modulation of nicotinamide adenine dinucleotide (NAD+). The invention also relates to methods of making such compounds and compositions. The invention relates to pharmaceutical compositions containing one or more NAD+ modulating compounds as a first ingredient in combination with one or more active pharmaceutical ingredients. Further, the invention relates to methods of using such compounds or compositions to promote the increase of intracellular levels of nicotinamide adenine dinucleotide (NAD+) in cells and tissues for treating diseases and/or improving cell and tissue survival.

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application62/822,456, filed Mar. 22, 2019, and U.S. Non-Provisional applicationSer. No. 16/362,130, filed Mar. 22, 2019, each of which is incorporatedherein by reference in its entirety.

BACKGROUND

Nicotinamide adenine dinucleotide (NAD) and related compounds are knownas essential coenzymes in cellular redox reactions in all livingorganisms. Several lines of evidence have also shown that NADparticipates in a number of important signaling pathways in mammaliancells, including poly(ADP-ribosyl)ation in DNA repair (Menissier deMurcia et al., EMBO J., (2003) 22, 2255-2263), mono-ADP-ribosylation inthe immune response and G protein-coupled signaling (Corda and DiGirolamo, EMBO J., (2003) 22, 1953-8), and the synthesis of cyclicADP-ribose and nicotinate adenine dinucleotide phosphate (NAADP) inintracellular calcium signaling (Lee, Annu. Rev. Pharmacol. Toxicol.,(2001) 41, 317-345). It has also been shown that NAD and its metabolitesplay an important role in transcriptional regulation (Lin and Guarente,Curr. Opin. Cell. Biol., (2003) 15, 241-246). In particular, thediscovery of Sir2 NAD-dependent deacetylase activity (e.g., Imai et al.,Nature, (2000) 403, 795-800; Landry et al., Biochem. Biophys. Res.Commun., (2000) 278, 685-690; Smith et al., Proc. Natl. Acad. Sci. USA,(2000) 97, 6658-6663) drew attention to this role of NAD.

Despite the advances in understanding the biology of NAD, there remainsa need for improved compositions and methods of using such compositionsfor pharmacologic intervention and/or manipulation of the NAD pathway inliving cells and tissues.

SUMMARY

The invention relates to compounds and compositions for modulation ofnicotinamide adenine dinucleotide (NAD+). In some embodiments, theinvention relates to methods of making such compounds and compositions.In some embodiments, the invention relates to pharmaceuticalcompositions containing one or more NAD+ modulating compounds as a firstingredient in combination with one or more active pharmaceuticalingredients. In further embodiments, the invention relates to methods ofusing such compounds or compositions to promote the increase ofintracellular levels of nicotinamide adenine dinucleotide (NAD+) incells and tissues for treating diseases and/or improving cell and tissuesurvival.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts NAD(H) normalized to total protein in treated AML12 cellscompared to untreated cells (first data column normalized to 1.0) forCompound A at 2 mM, 1 mM and 500 micromolar concentrations, and forCompound B at 2 mM, 1 mM, and 500 micromolar concentrations, showingthat both compounds possess NAD(H) boosting activity in AML12 cells.Compound A is Formula I, n=2. Compound B is Formula I, n=1.

DETAILED DESCRIPTION Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the meaning commonly understood by a person skilled in the art ofthe present disclosure. As used herein, the following terms have themeanings ascribed to them below, unless specified otherwise.

In this disclosure, “comprises,” “comprising,” “containing” and “having”and the like can have the meaning ascribed to them in U.S. patent lawand can mean “includes,” “including,” and the like; “consistingessentially of” or “consists essentially” likewise has the meaningascribed in U.S. patent law and the term is open-ended, allowing for thepresence of more than that which is recited so long as basic or novelcharacteristics of that which is recited is not changed by the presenceof more than that which is recited, but excludes prior art embodiments.

Ranges provided herein are understood to be shorthand for all of thevalues within the range. For example, a range of 1 to 50 is understoodto include any number, combination of numbers, or sub-range from thegroup consisting 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50.

The phrase “a” or “an” entity as used herein refers to one or more ofthat entity; for example, a compound refers to one or more compounds orat least one compound. As such, the terms “a” (or “an”), “one or more”,and “at least one” can be used interchangeably herein.

Unless specifically stated or obvious from context, as used herein, theterm “about” is understood as within a range of normal tolerance in theart, for example within 2 standard deviations of the mean. About can beunderstood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%,0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear fromcontext, all numerical values provided herein are modified by the termabout.

The terms “optional” or “optionally” as used herein means that asubsequently described event or circumstance may but need not occur, andthat the description includes instances where the event or circumstanceoccurs and instances in which it does not. For example, “optional bond”means that the bond may or may not be present, and that the descriptionincludes single, double, or triple bonds.

The term “purified,” as described herein, refers to the purity of agiven compound. For example, a compound is “purified” when the givencompound is a major component of the composition, i.e., at least about50% w/w pure. Thus, “purified” embraces at least about 50% w/w purity,at least about 60% w/w purity, at least about 70% purity, at least about80% purity, at least about 85% purity, at least about 90% purity, atleast about 92% purity, at least about 94% purity, at least about 96%purity, at least about 97% purity, at least about 98% purity, at leastabout 99% purity, at least about 99.5% purity, and at least about 99.9%purity, wherein “substantially pure” embraces at least about 97% purity,at least about 98% purity, at least about 99% purity, at least about99.5% purity, and at least about 99.9% purity.

The term “metabolite,” as described herein, refers to a compoundproduced in vivo after administration to a subject.

The term “salts,” as described herein, refers to a compound comprising acation and an anion, which can be produced by the protonation of aproton-accepting moiety and/or deprotonation of a proton-donatingmoiety. It should be noted that protonation of the proton-acceptingmoiety results in the formation of a cationic species in which thecharge is balanced by the presence of a physiological anion, whereasdeprotonation of the proton-donating moiety results in the formation ofan anionic species in which the charge is balanced by the presence of aphysiological cation.

The phrase “pharmaceutically acceptable salt” means a salt that ispharmaceutically acceptable. Examples of pharmaceutically acceptablesalts include, but are not limited to: (1) acid addition salts, formedwith inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like; or formedwith organic acids such as glycolic acid, pyruvic acid, lactic acid,malonic acid, malic acid, maleic acid, fumaric acid, tartaric acid,citric acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonicacid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid, lauryl sulfuric acid,gluconic acid, glutamic acid, salicylic acid, muconic acid, and the likeor (2) basic addition salts formed with the conjugate bases of any ofthe inorganic acids listed above, wherein the conjugate bases comprise acationic component selected from among Na⁺, K⁺, Mg²⁺, Ca²⁺,NH_(g)R_(4-g) ⁺, in which R is a C₁₋₃ alkyl and g is a number selectedfrom 0, 1, 2, 3, or 4. It should be understood that all references topharmaceutically acceptable salts include solvent addition forms(solvates) or crystal forms (polymorphs) as defined herein, of the sameacid addition salt.

The present invention also includes useful forms of the compounds of thepresent invention, such as metabolites, hydrates, solvates, prodrugs,salts, in particular pharmaceutically acceptable salts, and/orco-precipitates.

The compounds of the present invention can exist as a hydrate, or as asolvate, wherein the compounds of the present invention form a crystalthat contains molecules of polar solvents, in particular water, methanolor ethanol, for example, as structural element of the crystal lattice ofthe compounds. The molecules of polar solvents, in particular water, maybe present in a stoichiometric or non-stoichiometric ratio with themolecules of the compound. In the case of stoichiometric solvates, e.g.,a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta-etc. solvates or hydrates, respectively, are possible. The presentinvention includes all such hydrates or solvates.

Further, it is possible for the compounds of the present invention toexist in free form, e.g., as a free base, or as a free acid, or as azwitterion, or to exist in the form of a salt. Said salt may be anysalt, either an organic or inorganic addition salt, particularly anypharmaceutically acceptable organic or inorganic addition salt, which iscustomarily used in pharmacy, or which is used, for example, forisolating or purifying the compounds of the present invention.

The term “subject” to which administration is contemplated includes, butis not limited to, humans (i.e., a male or female of any age group,e.g., a pediatric subject (e.g., infant, child, adolescent) or adultsubject (e.g., young adult, middle-aged adult or senior adult)) and/orother primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals,including commercially relevant mammals such as cattle, pigs, horses,sheep, goats, cats, and/or dogs; and/or birds, including commerciallyrelevant birds such as chickens, ducks, geese, quail, and/or turkeys.

The terms “treatment”, “treating”, “palliating” and “ameliorating” areused interchangeably herein. These terms refer to an approach forobtaining beneficial or desired results including, but not limited to,therapeutic benefit and/or a prophylactic benefit. By therapeuticbenefit is meant eradication or amelioration of the underlying disorderbeing treated. Also, a therapeutic benefit is achieved with theeradication or amelioration of one or more of the physiological symptomsassociated with the underlying disorder such that an improvement isobserved in the patient, notwithstanding that the patient can still beafflicted with the underlying disorder. For prophylactic benefit, thepharmaceutical compounds and/or compositions can be administered to apatient at risk of developing a particular disease, or to a patientreporting one or more of the physiological symptoms of a disease, eventhough a diagnosis of this disease may not have been made.

The term “preparation” or “dosage form” is intended to include bothsolid and liquid formulations of the active compound and one skilled inthe art will appreciate that an active ingredient can exist in differentpreparations depending on the desired dose and pharmacokineticparameters.

The term “excipient” as used herein refers to a compound that is used toprepare a pharmaceutical composition, and is generally safe, non-toxicand neither biologically nor otherwise undesirable, and includesexcipients that are acceptable for veterinary use as well as humanpharmaceutical use.

Compounds, Compositions and Methods of Treatment

Provided herein is a compound having the structure:

and salts thereof.

Also provided herein are compositions comprising one or morepharmaceutically acceptable excipients and one or more compounds, and/orsalts, thereof, wherein the compound has a structure represented byFormula I:

wherein n is an integer from 1 to 3.

Provided herein are compositions comprising one or more additionalactive pharmaceutical ingredients and one or more compounds, and/or oneor more salts thereof, wherein the compound has a structure representedby Formula I:

wherein n is an integer from 1 to 3.

In some embodiments, n is 1. In other embodiments, n is 2. In yet otherembodiments, n is 3.

In some embodiments, the composition is in a solid form selected from atablet, a pill, a capsule, a caplet, a troche, granules, powders,sachet, dry powder inhalation form, a chewable, a pastille, and alozenge. In certain embodiments, the composition is in the form of atablet. In other embodiments, the composition is in a form of a hard orsoft gelatin capsule.

In some embodiments, the compound is in an amorphous solid form. Inother embodiments, the compound is in a crystalline solid form.

In some embodiments, the amount of the compound of Formula I in thecomposition is about 0.001% by weight to about 10% by weight, about0.01% by weight to about 10% by weight, about 0.1% by weight to about 8%by weight, about 0.25% by weight to about 8% by weight, about 0.5% byweight to about 5% by weight, about 0.5% by weight to about 3% byweight, or about 0.1% by weight to about 1% by weight, preferably about0.5% by weight of the composition. In certain embodiments, the amount ofthe compound of Formula I in the composition is about 0.25% by weight ofthe composition.

In some embodiments, the pharmaceutically acceptable excipient isselected from an anti-adherent, binder, coating, dye, disintegrant,flavoring agent, glidant, lubricant, preservative, sorbent, sweetener,syrups, elixirs, dispersant, diluent, filler, granulating agent, coatingagent, wax, suspending agent, wetting agent, thickener and vehicle andcombinations thereof. In some embodiments, the excipient is a solidexcipient.

In some embodiments, the pharmaceutically acceptable excipient ispresent in an amount of at least about 5% by weight, at least about 10%by weight, at least about 15% by weight, at least about 20% by weight,at least about 25% by weight, at least about 30% by weight, at leastabout 35% by weight, at least about 40% by weight, at least about 45% byweight, at least about 50% by weight, at least about 55% by weight, orat least about 60% by weight of the composition. In some embodiments,the pharmaceutically acceptable excipient is present in an amount of atleast about 20% by weight, at least about 25% by weight, at least about30% by weight, at least about 35% by weight, or at least about 40% byweight, preferably at least about 30% by weight of the composition. Inother embodiments, the pharmaceutically acceptable excipient is presentin an amount of at least about 50% by weight of the composition.

In some embodiments, the amount of the compound of Formula I relative tothe amount of one or more additional active pharmaceutical ingredientsin the composition ranges from about 0.001% by weight to less that about50% by weight, about 0.01% by weight to about 45% by weight, about 0.05%by weight to about 40% by weight, about 0.1% by weight to about 30% byweight, about 0.5% by weight to about 30% by weight, about 1% by weightto about 30% by weight, about 1.5% by weight to about 20% by weight,about 2% by weight to about 20% by weight, about 2.5% by weight to about20% by weight, about 3% by weight to about 20% by weight, or about 0.5%by weight to about 5% by weight, preferably about 0.5% by weight toabout 1.5% by weight of the composition. In certain embodiments, theamount of the compound of Formula I relative to the amount of one ormore additional active pharmaceutical ingredients in the composition is0.5% by weight of the composition. In other embodiments, the amount ofthe compound of Formula I relative to the amount of one or moreadditional active pharmaceutical ingredients in the composition is 1.5%by weight of the composition.

In some embodiments, the amount of the compound of Formula I relative tothe amount of one or more additional active pharmaceutical ingredientsis greater than zero. The term “greater than zero” refers to an amountthat is at the lower limit of detection by any quantitative means knownin the art. Non-limiting examples of methods for quantifying a chemicalsubstance include chromatography (liquid LC, high-performance liquidHPLC, gas G), electrospray ionization (ESI), atmospheric pressurechemical ionization (APCI), and atmospheric pressure photoionization(APPI). These separation methods are coupled to a mass analyzer thatidentifies the compound being measured. Mass spectrometry techniquesinclude triple quadrupole (QQQ), ion trap (IT), triple quadrupole-linearion traps (QTrap), time of flight (TOF), triple quadrupole-time offlight (Q-TOF), Orbitrap, and Fourier transform-ion cyclotron resonance(FT-ICR). See, Roskar, R. et al. Analytical Methods for Quantificationof Drug Metabolites in Biological Samples 2012, pgs. 87-91.

In some embodiments, the active pharmaceutical ingredient is selectedfrom compounds in the NAD+ pathway, such as nicotinic acid (NA),nicotinamide (Nam), nicotinamide mononucleotide (NMN), nicotinamideriboside (NR), nicotinic acid mononucleotide (NaMN), nicotinic acidriboside (NAR), nicotinamide adenine dinucleotide (NAD⁺/NADH),nicotinamide adenine dinucleotide phosphate (NADP), and nicotinic acidadenine dinucleotide (NaAD). In some embodiments, the activepharmaceutical ingredient is an amorphous solid. In some embodiments,the active pharmaceutical ingredient is a crystalline solid. In someembodiments, the active pharmaceutical ingredient is amorphous NMN.

In some embodiments, the active pharmaceutical ingredient is selectedfrom anti-aging compounds such as antioxidants (e.g., CoQ10, vitamin C,Vitamin E), peptides such as Matrixyl (palmitoyl pentapeptide-3),Argireline (acetyl hexapeptide-3), Vitamin A, related retinoids, andanti-aging sunscreens such as Helioplex and Mexoryl SX (ecamsule).

In some embodiments, the active pharmaceutical ingredient is selectedfrom pain relievers and inflammation-reducing agents, such asacetaminophen, duloxetine, aspirin, ibuprofen, naproxen, diclofenac, anddiclofenac-misoprostol. Other NSAID active pharmaceutical ingredientsinclude celecoxib, piroxicam, indomethacin, meloxicam, ketoprofen,sulindac, diflunisal, nabumetone, oxaprozin, tolmetin, salsalate,etodolac, fenoprofen, flurbiprofen, ketorolac, meclofenamate, andmefenamic acid.

In some embodiments, the active pharmaceutical ingredient is selectedfrom compounds used to treat dermatitis, such as triamcinolone,clobetasol, betamethasone, hydrocortisone, fluocinonide, andprednisolone. In other embodiments, the active pharmaceutical ingredientis selected from compounds used to treat wounds, such as silversulfadiazine, santyl collagenase, chlorhexidine, urea, venelex, andlevicyn.

In some embodiments, the active pharmaceutical ingredient is selectedfrom senolytics such as dasatinib, quercetin, cortisol, corticosterone,metformin, resveratrol, apigenin, wogonin, kaempferol, rapamycin,ruxolitinib, tofacitinib, simvastatin, and navitoclax.

In some embodiments, the active pharmaceutical ingredient is selectedfrom compounds used to treat cardiovascular diseases and disorders, suchas amiloride, bumetanide, chlorothiazide, chlorthalidone, furosemide,hydro-chlorothiazide, indapamide, and spironolactone.

In some embodiments, the active pharmaceutical ingredient is selectedfrom a serotonin reuptake inhibitor (SRI), a 5HT2 receptor antagonist,an anticonvulsant, a norepinephrine reuptake inhibitor, analpha-adrenoreceptor antagonist, an NK-3 antagonist, an NK-1 receptorantagonist, a PDE4 inhibitor, an Neuropeptide Y5 Receptor Antagonists, aD4 receptor antagonist, a 5HT1A receptor antagonist, a 5HT1D receptorantagonist, a CRF antagonist, a monoamine oxidase inhibitor, and asedative-hypnotic drug.

In some embodiments, the SRI is a selective SRI selected fromfluoxetine, norfluoxetine, nefazodone, hydroxynefazodone, oxonefazodone,duloxetine, venlafaxine, milnacipran, citalopram, fluvoxamine,paroxetine and sertraline. In some embodiments, the sedative-hypnoticdrug is selected from alprazolam, chlordiazepoxide, clonazepam,chlorazepate, clobazam, diazepam, halazepam, lorazepam, oxazepamprazepam, Zolpidem, and barbiturates. In some embodiments, the 5HT1Areceptor antagonist is selected from buspirone, flesinoxan, gepirone andipsapirone.

In certain embodiments, the norepinephrine reuptake inhibitor isselected from tertiary tricyclics such as amitriptyline, clomipramine,doxepin, imipramine and trimipramine. In other embodiments, thenorepinephrine reuptake inhibitor is selected from secondary aminetricyclics such as amoxapine, desipramine, maprotiline, nortriptylineand protriptyline.

In some embodiments, the monoamine oxidase inhibitor is selected fromisocarboxazid, phenelzine, tranylcypromine, selegiline and moclobemide.

In other embodiments, the active pharmaceutical ingredient is achemotherapeutic agent selected from1-amino-4-phenylamino-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate(acid blue 25),1-amino-4-[4-hydroxyphenyl-amino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate,1-amino-4-[4-aminophenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate,1-amino-4-[1-naphthylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate,1-amino-4-[4-fluoro-2-carboxyphenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate,1-amino-4-[2-anthracenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate,ABT-263, afatinib dimaleate, axitinib, aminoglutethimide, amsacrine,anastrozole, APCP, asparaginase, AZD5363, Bacillus Calmette-Guérinvaccine (bcg), bicalutamide, bleomycin, bortezomib, β-methylene-ADP(AOPCP), buserelin, busulfan, cabazitaxel, cabozantinib, campothecin,capecitabine, carboplatin, carfilzomib, carmustine, ceritinib,chlorambucil, chloroquine, cisplatin, cladribine, clodronate,cobimetinib, colchicine, crizotinib, cyclophosphamide, cyproterone,cytarabine, dacarbazine, dactinomycin, daunorubicin, demethoxyviridin,dexamethasone, dichloroacetate, dienestrol, diethylstilbestrol,docetaxel, doxorubicin, epirubicin, eribulin, erlotinib, estradiol,estramustine, etoposide, everolimus, exemestane, filgrastim,fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide,gefitinib, gemcitabine, genistein, goserelin, GSK1120212, hydroxyurea,idarubicin, ifosfamide, imatinib, interferon, irinotecan, ixabepilone,lenalidomide, letrozole, leucovorin, leuprolide, levamisole, lomustine,lonidamine, mechlorethamine, medroxyprogesterone, megestrol, melphalan,mercaptopurine, mesna, metformin, methotrexate, miltefosine, mitomycin,mitotane, mitoxantrone, MK-2206, mutamycin,N-(4-sulfamoylphenylcarbamothioyl) pivalamide, NF279, NF449, nilutamide,nocodazole, octreotide, olaparib, oxaliplatin, paclitaxel, pamidronate,pazopanib, pemexetred, pentostatin, perifosine, PF-04691502, plicamycin,pomalidomide, porfimer, PPADS, procarbazine, quercetin, raltitrexed,ramucirumab, reactive blue 2, rituximab, rolofylline, romidepsin,rucaparib, selumetinib, sirolimus, sodium 2,4-dinitrobenzenesulfonate,sorafenib, streptozocin, sunitinib, suramin, talazoparib, tamoxifen,temozolomide, temsirolimus, teniposide, testosterone, thalidomide,thioguanine, thiotepa, titanocene dichloride, tonapofylline, topotecan,trametinib, trastuzumab, tretinoin, veliparib, vinblastine, vincristine,vindesine, vinorelbine, and vorinostat (SAHA).

In other embodiments, suitable chemotherapeutic agents include: ABT-263,dexamethasone, 5-fluorouracil, PF-04691502, romidepsin, and vorinostat(SAHA). In other embodiments, chemotherapeutic agents include:1-amino-4-phenylamino-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate(acid blue 25),1-amino-4-[4-hydroxyphenyl-amino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate,1-amino-4-[4-aminophenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate,1-amino-4-[1-naphthylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate,1-amino-4-[4-fluoro-2-carboxyphenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate,1-amino-4-[2-anthracenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate,APCP, β-methylene-ADP (AOPCP), capecitabine, cladribine, cytarabine,fludarabine, doxorubicin, gemcitabine,N-(4-sulfamoylphenylcarbamothioyl) pivalamide, NF279, NF449, PPADS,quercetin, reactive blue 2, rolofylline sodium2,4-dinitrobenzenesulfonate, sumarin, and tonapofylline.

Other types of chemotherapeutic agents include immuno-oncology agentssuch as abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomabmafenatox, apolizumab, blinatumomab, BMS-936559, catumaxomab,durvalumab, epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin,intelumumab, ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A,nivolumab, obinutuzumab, ocaratuzumab, ofatumumab, olatatumab,pembrolizumab, pidilizumab, rituximab, ticilimumab, samalizumab, andtremelimumab.

In some embodiments, the active pharmaceutical ingredient is selectedfrom PARP inhibitors that are known to repair DNA damage, such asolaparib, veliparib, niraparib, NMS-P118, talazoparib, and rucaparib.

In some embodiments, the active pharmaceutical ingredient is selectedfrom agents for treating neurodegenerative diseases such as amantadine,apomorphine, baclofen, carbidopa, dantrolene, donepezil, entacapone,galantamine, levodopa, memantine, pramipexole, rasagiline, riluzole,rivastigmine, ropinirole, selegiline, tacrine, tetrabenazine,tizanidine, and tolcapone.

In some embodiments, the active pharmaceutical ingredient is selectedfrom agents for treating neuropathy, such as gabapentin, levocarnitine,duloxetine, carbamazepine, capsaicin, pregabalin, and qutenza.

In some embodiments, the active pharmaceutical ingredient is selectedfrom agents for treating thrombotic disorders, such as heparin,Activase, alteplase, argatroban, Acova, urokinase, and Abbokinase.

In some embodiments, the active pharmaceutical ingredient is selectedfrom agents for treating obesity and weight gain, such as phentermine,Adipex-P, topiramate, Belviq, Contrave, Desoxyn, Alli, phendimetrazine,Xenical, orlistat, and Tenuate.

In some embodiments, the active pharmaceutical ingredient is selectedfrom agents for treating diabetes and regulating blood glucose levels,such as chlorpropamide, tolbutamide, tolazamide, glimepiride, glyburide,glipizide, gliclazide, metformin, miglitol, acarbose, pioglitazone,rosiglitazone, repaglinide, nateglinide, exenatide, liraglutide,dulaglutide, lixisenatide, semaglutide, saxagliptin, sitagliptin,linagliptin, alogliptin, canagliflozin, dapagliflozin, empagliflozin,and ertugliflozin.

In some embodiments, the active pharmaceutical ingredient is selectedfrom agents for treating circadian rhythm disorders, such as melatonin,rozerem, benzodiazapines, Ambien, Sonata, Lunesta, Belsomra, andProvigil.

Also disclosed herein is a compound of Formula II:

wherein m is 2 or 3, or a salt thereof. In some embodiments, m is 2,while in other embodiments, m is 3.

In some embodiments, the one or more active pharmaceutical ingredientsare selected from nicotinic acid (NA), nicotinamide (Nam), nicotinamidemononucleotide (NMN), nicotinamide riboside (NR), nicotinic acidmononucleotide (NaMN), nicotinic acid riboside (NAR), nicotinamideadenine dinucleotide (NAD⁺/NADH), nicotinamide adenine dinucleotidephosphate (NADP), nicotinic acid adenine dinucleotide (NaAD), and one ormore compounds of Formula II:

wherein m is 2 or 3, and one or more salts thereof, and combinationsthereof.

The present invention includes the use of pharmaceutically acceptablesalts of compounds of the invention in the compositions and methods ofthe present invention. In certain embodiments, contemplated salts of theinvention include, but are not limited to, alkyl, dialkyl, trialkyl ortetra-alkyl ammonium salts. In certain embodiments, contemplated saltsof the invention include, but are not limited to, L-arginine,benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol,diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine,ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium,L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine,potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine,tromethamine, and zinc salts.

In certain embodiments, the compound is a salt with an anion selectedfrom acetate, triflate, halide, trifluoroacetate, or formate. In otherembodiments, if the disclosed compound is in contact with a media, e.g.,aqueous media, the anion can be selected from, for example, OH⁻, H₂PO₄⁻, HPO₄ ²⁻, HSO₄ ⁻, SO₄ ²⁻, NO₃ ⁻, HCO₃ ⁻, and CO₃ ²⁻.

In some embodiments, the disclosed compounds are in the form of anegatively charged phosphate, which may form a salt with any suitablecation. The cation can alter as the compound is isolated or transferredinto media with different anionic species. For example, a disclosedcompound may be in the form of a phosphate salt that is apharmaceutically acceptable salt as described herein. In certainembodiments, the cation can be selected from Li⁺, Na⁺, K⁺, Mg²⁺, andCa²⁺.

Provided herein are methods of increasing NAD+ levels in a subject inneed thereof, comprising administering a compound, or a salt thereof,wherein the compound is one disclosed herein.

Provided herein are methods of treating a disease or disorder associatedwith NAD+ biosynthesis, comprising administering a compound, or a saltthereof, wherein the compound is one disclosed herein.

Provided herein is any composition as described herein for use inincreasing NAD+ levels. In one embodiment the composition comprises acompound of Formula I.

Diseases, Disorders and Conditions

Provided herein are methods for using the disclosed compounds andpharmaceutical compositions thereof. The disclosed compounds andpharmaceutical compositions thereof can be useful for a variety oftherapeutic applications including, for example, treating and/orreducing a wide variety of diseases and disorders including, forexample, diseases or disorders related to aging or stress, diabetes,obesity, neurodegenerative diseases, cardiovascular disease, bloodclotting disorders, inflammation, cancer, and/or flushing, etc. Themethods comprise administering to a subject in need thereof a disclosedcompound and/or pharmaceutical composition thereof.

In other embodiments, the disclosed compounds and/or a pharmaceuticalcomposition thereof can be used to treat skin conditions. Exemplary skinconditions that may be treated in accordance with the methods describedherein include disorders or diseases associated with or caused byinflammation, sun damage, or natural aging. For example, thecompositions find utility in the treatment of contact dermatitis(including irritant contact dermatitis and allergic contact dermatitis),atopic dermatitis (also known as allergic eczema), actinic keratosis,keratinization disorders (including eczema), epidermolysis bullosadiseases (including penfigus), exfoliative dermatitis, seborrheicdermatitis, erythemas (including erythema multiforme and erythemanodosum), damage caused by the sun or other light sources, discoid lupuserythematosus, dermatomyositis, psoriasis, skin cancer and the effectsof natural aging. In other embodiments, the disclosed compounds andpharmaceutical compositions thereof may be used for the treatment ofwounds and/or burns to promote healing, including, for example, first-,second- or third-degree burns and/or thermal, chemical or electricalburns.

The disclosed compounds and pharmaceutical compositions thereof can alsobe administered to a subject suffering from an acute disease, e.g.,damage to an organ or tissue, e.g., a subject suffering from stroke ormyocardial infarction or a subject suffering from a spinal cord injury.The disclosed compounds and pharmaceutical compositions thereof may alsobe used to repair an alcoholic's liver.

In certain embodiments, a compound or pharmaceutical composition asdisclosed herein may be used for treating or preventing a disease orcondition induced or exacerbated by cellular senescence in a subject;methods for decreasing the rate of senescence of a subject, e.g., afteronset of senescence; methods for extending the lifespan of a subject;methods for treating or preventing a disease or condition relating tolifespan; methods for treating or preventing a disease or conditionrelating to the proliferative capacity of cells; and methods fortreating or preventing a disease or condition resulting from cell damageor death. In certain embodiments, the method does not act by decreasingthe rate of occurrence of diseases that shorten the lifespan of asubject. In certain embodiments, a method does not act by reducing thelethality caused by a disease, such as cancer.

In certain embodiments, a compound or pharmaceutical composition asdisclosed herein may be administered to a subject in order to generallyincrease the lifespan of its cells and to protect its cells againststress and/or against apoptosis. Treating a subject with a compounddescribed herein may be similar to subjecting the subject to hormesis,i.e., mild stress that is beneficial to organisms and may extend theirlifespan.

In other embodiments, provided herein is a method for treating acardiovascular disease by administering to a subject in need thereof adisclosed compound and/or a pharmaceutical composition thereof.Cardiovascular diseases that can be treated using the disclosedcompounds and pharmaceutical compositions thereof include cardiomyopathyor myocarditis; such as idiopathic cardiomyopathy, metaboliccardiomyopathy, alcoholic cardiomyopathy, drug-induced cardiomyopathy,ischemic cardiomyopathy, and hypertensive cardiomyopathy. Also treatableusing compositions and methods described herein are atheromatousdisorders of the major blood vessels (macrovascular disease) such as theaorta, the coronary arteries, the carotid arteries, the cerebrovasculararteries, the renal arteries, the iliac arteries, the femoral arteries,and the popliteal arteries. Other vascular diseases that can be treatedinclude those related to platelet aggregation, the retinal arterioles,the glomerular arterioles, the vasa nervorum, cardiac arterioles, andassociated capillary beds of the eye, the kidney, the heart, and thecentral and peripheral nervous systems. The disclosed compounds andpharmaceutical compositions thereof may also be used for increasing HDLlevels in plasma of an individual.

The disclosed compounds and pharmaceutical compositions thereof may beadministered to subjects who have recently received or are likely toreceive a dose of radiation or toxin. In one embodiment, the dose ofradiation or toxin is received as part of a work-related or medicalprocedure, e.g., working in a nuclear power plant, flying an airplane,an X-ray, CAT scan, or the administration of a radioactive dye formedical imaging; in such an embodiment, the compound is administered asa prophylactic measure. In other embodiments, the radiation or toxinexposure is received unintentionally, e.g., as a result of an industrialaccident, habitation in a location of natural radiation, terrorist act,or act of war involving radioactive or toxic material. In such a case,the disclosed compounds and pharmaceutical compositions thereof arepreferably administered as soon as possible after the exposure toinhibit apoptosis and the subsequent development of acute radiationsyndrome.

In other embodiments, the disclosed compounds and pharmaceuticalcompositions thereof may be useful for treating age-related disorders,such as, for example, cancer. Exemplary cancers that may be treatedusing the disclosed compounds and pharmaceutical compositions thereofinclude those of the brain and kidney; hormone-dependent cancersincluding breast, prostate, testicular, and ovarian cancers; lymphomas,and leukemias. Other diseases that can be treated include autoimmunediseases, e.g., systemic lupus erythematosus, scleroderma, andarthritis, in which autoimmune cells should be removed. Viral infectionssuch as herpes, HIV, adenovirus, and HTLV-1 associated malignant andbenign disorders can also be treated by administration of the disclosedcompounds and pharmaceutical compositions thereof.

In some embodiments, the disclosed compounds and pharmaceuticalcompositions thereof can be used to treat patients suffering fromneurodegenerative diseases, and traumatic or mechanical injury to thecentral nervous system (CNS) or peripheral nervous system (PNS).Examples of neurodegenerative diseases include, but are not limited to,ataxia, Alzheimer's disease (AD), Parkinson's disease (PD), Huntingtondisease (HD), amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease),diffuse Lewy body disease, chorea-acanthocytosis, primary lateralsclerosis, ocular diseases (ocular neuritis), chemotherapy-inducedneuropathies (e.g., from vincristine, paclitaxel, bortezomib),diabetes-induced neuropathies, and Friedreich's ataxia.

In other embodiments, the disclosed compounds and pharmaceuticalcompositions thereof may be used for reducing appetite and/or increasingsatiety, thereby causing weight loss or avoidance of weight gain. Asubject in need of such a treatment may be a subject who is overweight,obese or a subject likely to become overweight or obese.

In other embodiments, the disclosed compounds and pharmaceuticalcompositions thereof may be used to treat a subject who has cachexia ormay be likely to develop cachexia. A method may further comprisemonitoring in the subject the state of the disease. Methods forpromoting appetite and/or weight gain may include, for example, prioridentifying a subject as being in need of decreased fat or lipidmetabolism, e.g., by weighing the subject, determining the BMI of thesubject. The method may also include monitoring the subject, e.g.,during and/or after administration of the disclosed compounds orpharmaceutical compositions thereof. The administering can include oneor more dosages, e.g., delivered in boluses or continuously. Monitoringcan include evaluating a hormone or a metabolite. Exemplary hormonesinclude leptin, adiponectin, resistin, and insulin. Exemplarymetabolites include triglycerides, cholesterol, and fatty acids.

In some embodiments, the disclosed compounds and pharmaceuticalcompositions thereof may be used for treating a metabolic disorder, suchas insulin-resistance, a pre-diabetic state, type II diabetes, and/orcomplications thereof.

Administration of the disclosed compounds and pharmaceuticalcompositions thereof may increase insulin sensitivity and/or decreaseinsulin levels in a subject. A subject in need of such a treatment maybe a subject who has insulin resistance or other precursor symptom oftype II diabetes, who has type II diabetes, or who is likely to developany of these conditions. For example, the subject may be a subjecthaving insulin resistance, e.g., having high circulating levels ofinsulin and/or associated conditions, such as hyperlipidemia,dyslipogenesis, hypercholesterolemia, impaired glucose tolerance, highblood glucose sugar level, other manifestations of syndrome X,hypertension, atherosclerosis, and lipodystrophy.

Provided herein is a process for regulating the concentration of bloodglucose in a mammal. As utilized herein, regulating the concentration ofblood glucose refers to any increase, decrease, and/or maintenance in orof the concentration of blood glucose as compared to a previouslydetermined level.

The methods of treatment disclosed herein are also directed to methodsof regulating the circadian clock, thereby regulating or affectingbiological functions that are regulated by (sometimes also said to beaffected by, affiliated with, or mediated by) the activity of thecircadian clock. Typically, these biological functions display a patternof activity and inactivity that is generally repeated approximatelyevery 24 hours, oscillating between “active” and “inactive” statesduring the 24 hour period.

Thus, the present invention provides methods of regulating the activityof the circadian clock by administering to a mammal in need thereof acompound or pharmaceutical composition as disclosed herein. Generally,the regulation of the activity of the circadian clock is the result ofthe regulation of CLOCK:BMAL1, which is achieved according to thepresent methods by regulating the activity of SIRT1. The activity ofSIRT1 is generally regulated according to the present methods byadministration of a compound or pharmaceutical composition as disclosedherein, and in certain embodiments, by administration of a compound thataffects the NAD+ pathway. The regulation of the circadian clock therebypermits regulation of activities mediated by the circadian clock.

According to the present invention, the activity of the circadian clockmay be increased, decreased, or maintained by the administration of acompound or pharmaceutical composition as disclosed herein. Accordingly,biological functions (sometimes also referred to as biologicalactivities) that are regulated by the activity of the circadian clockmay also be increased, decreased, or maintained. In addition, thesebiological functions may also be time shifted; that is to say, anactivity that typically occurs during a particular period, such as forexample, during daytime or daylight hours (sometimes also referred to asthe light cycle) or during the night or nighttime hours (sometimes alsoreferred to as the dark cycle) may be shifted such that the activityoccurs during the dark or light cycle, respectively, instead.

Pharmaceutical Formulations

The compounds of this invention are formulated with conventionalcarriers and excipients, which can be selected in accord with ordinarypractice. Tablets can contain excipients, glidants, fillers, binders andthe like. All formulations will optionally contain excipients such asthose set forth in the “Handbook of Pharmaceutical Excipients” (1986).Suitable excipients are also listed in the US Food and DrugAdministration Inactive Ingredients Database. Excipients includeascorbic acid and other antioxidants, chelating agents such as EDTA,carbohydrates such as dextran, hydroxyalkylcellulose,hydroxyalkylmethylcellulose, stearic acid and the like. The pH of theformulations can range from about 3 to about 11, but is ordinarily about7 to about 10.

While it is possible for the active ingredients to be administeredalone, it may be preferable to present them as pharmaceuticalformulations. The formulations, both for veterinary and for human use,of the invention comprise at least one active ingredient, as abovedefined, together with one or more acceptable carriers therefor andoptionally other therapeutic ingredients. The carrier(s) must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and physiologically innocuous to the recipientthereof.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of a subject without excessive toxicity, irritation,allergic response, or other problem or complication, commensurate with areasonable benefit/risk ratio.

The phrase “pharmaceutically acceptable carrier” as used herein means apharmaceutically acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, solvent or encapsulatingmaterial. Each carrier must be “acceptable” in the sense of beingcompatible with the other ingredients of the formulation and notinjurious to the subject. Some examples of materials which can serve aspharmaceutically acceptable carriers include: (1) sugars, such aslactose, glucose and sucrose; (2) starches, such as corn starch andpotato starch; (3) cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients,such as cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer'ssolution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21)other non-toxic compatible substances employed in pharmaceuticalformulations.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tablets,each containing a predetermined amount of the active ingredient as apowder or granules. The active ingredient may also be administered as abolus, electuary or paste.

A tablet is made by compression or molding, optionally with one or moreaccessory ingredients. Compressed tablets may be prepared by compressingin a suitable machine the active ingredient in a free-flowing form suchas a powder or granules, optionally mixed with a binder, lubricant,inert diluent, preservative, surface active or dispersing agent. Moldedtablets may be made by molding in a suitable machine a mixture of thepowdered active ingredient moistened with an inert liquid diluent. Thetablets may optionally be coated or scored and optionally are formulatedso as to provide slow or controlled release of the active ingredienttherefrom.

Pharmaceutical formulations according to the present invention comprisea compound according to the invention together with one or morepharmaceutically acceptable carriers or excipients and optionally othertherapeutic agents. Pharmaceutical formulations containing the activeingredient may be in any form suitable for the intended method ofadministration. When intended for oral use for example, tablets,troches, lozenges, aqueous or oil suspensions, dispersible powders orgranules, emulsions, hard or soft capsules, syrups or elixirs may beprepared. Compositions intended for oral use may be prepared accordingto any method known to the art for the manufacture of pharmaceuticalcompositions, and such compositions may contain one or more agentsincluding sweetening agents, flavoring agents, coloring agents andpreserving agents, in order to provide a palatable preparation. Tabletscontaining the active ingredient in admixture with non-toxicpharmaceutically acceptable excipient which are suitable for manufactureof tablets are acceptable. These excipients may be, for example, inertdiluents, such as calcium or sodium carbonate, lactose, calcium orsodium phosphate; granulating and disintegrating agents, such as maizestarch, or alginic acid; binding agents, such as starch, gelatin oracacia; and lubricating agents, such as magnesium stearate, stearic acidor talc. Tablets may be uncoated or may be coated by known techniques,including microencapsulation, to delay disintegration and adsorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate alone or with a wax may be employed.

Formulations for oral use may be also presented as hard gelatin capsuleswhere the active ingredient is mixed with an inert solid diluent, forexample calcium phosphate or kaolin, or as soft gelatin capsules whereinthe active ingredient is mixed with water or an oil medium, such aspeanut oil, liquid paraffin or olive oil.

Aqueous suspensions of the invention contain the active material(s) inadmixture with excipients suitable for the manufacture of aqueoussuspensions. Such excipients include a suspending agent, such as sodiumcarboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;and dispersing or wetting agents such as a naturally-occurringphosphatide (e.g., lecithin), a condensation product of an alkyleneoxide with a fatty acid (e.g., polyoxyethylene stearate), a condensationproduct of ethylene oxide with a long chain aliphatic alcohol (e.g.,heptadecaethyleneoxycetanol), a condensation product of ethylene oxidewith a partial ester derived from a fatty acid and a hexitol anhydride(e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension mayalso contain one or more preservatives such as ethyl or n-propylp-hydroxy-benzoate, one or more coloring agents, one or more flavoringagents and one or more sweetening agents, such as sucrose or saccharin.

Dispersible powders and granules of the invention suitable forpreparation of an aqueous suspension by the addition of water providethe active ingredient in admixture with a dispersing or wetting agent, asuspending agent, and one or more preservatives. Suitable dispersing orwetting agents and suspending agents are exemplified by those disclosedabove. Additional excipients, for example sweetening, flavoring andcoloring agents, may also be present.

The amount of active ingredient that may be combined with the carriermaterial to produce a single dosage form will vary depending upon thesubject treated and the particular mode of administration. For example,a time-release formulation intended for oral administration to humansmay contain approximately 1 to approximately 1000 mg of active materialcompounded with an appropriate and convenient amount of carrier materialwhich may vary from about 5% to about 95% of the total compositions(weight:weight). The pharmaceutical composition can be prepared toprovide easily measurable amounts for administration.

Formulations suitable for intrapulmonary or nasal administration have aparticle size for example in the range of about 0.1 to about 500microns, such as about 0.5, about 1, about 30, or about 35 microns etc.,which is administered by rapid inhalation through the nasal passage orby inhalation through the mouth so as to reach the alveolar sacs.Suitable formulations include aqueous or oily solutions of the activeingredient. Formulations suitable for aerosol or dry powderadministration may be prepared according to conventional methods and maybe delivered with other therapeutic agents.

The formulations are presented in unit-dose or multi-dose containers,for example sealed ampoules and vials, and may be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example water for injection, immediatelyprior to use. Extemporaneous injection solutions and suspensions areprepared from sterile powders, granules and tablets of the kindpreviously described. Preferred unit dosage formulations are thosecontaining a daily dose or unit daily sub-dose, as herein above recited,or an appropriate fraction thereof, of the active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations of this invention may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavoring agents.

While the foregoing written description of the invention enables one ofordinary skill to make and use what is considered presently to be thebest mode thereof, those of ordinary skill will understand andappreciate the existence of variations, combinations, and equivalents ofthe specific embodiment, method, and examples herein. The inventionshould therefore not be limited by the above described embodiment,method, and examples, but by all embodiments and methods within thescope and spirit of the invention.

It is to be understood that wherever values and ranges are providedherein, all values and ranges encompassed by these values and ranges,are meant to be encompassed within the scope of the present invention.Moreover, all values that fall within these ranges, as well as the upperor lower limits of a range of values, are also contemplated by thepresent application.

INCORPORATION BY REFERENCE

All US patents and US and PCT published patent applications andnon-patent literature mentioned in this specification are hereinincorporated by reference to the same extent as if each independentpatent and publication was specifically and individually indicated to beincorporated by reference.

EXAMPLES

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, numerous equivalents to thespecific procedures, embodiments, claims, and examples described herein.Such equivalents are considered to be within the scope of this inventionand covered by the claims appended hereto. For example, it should beunderstood, that modifications in reaction conditions, including but notlimited to reaction times, reaction size/volume, and experimentalreagents, such as solvents, catalysts, pressures, atmosphericconditions, e.g., nitrogen atmosphere, and reducing/oxidizing agents,with art-recognized alternatives and using no more than routineexperimentation, are within the scope of the present application.

The recitation of a listing of elements in any definition of a variableherein includes definitions of that variable as any single element orcombination (or sub-combination) of listed elements. The recitation ofan embodiment herein includes that embodiment as any single embodimentor in combination with any other embodiments or portions thereof. Unlessnoted otherwise, the starting materials for the synthesis describedherein were obtained from commercial sources or known syntheticprocedures and were used without further purification.

General Synthetic Scheme

Preparation ofbis(((2R,3S,4R,5R)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)phosphate acetate

NR Triflate (5.00 g, 12.38 mmoles) was placed into a 100 ml 1-necked24/40 round bottomed flask and placed under argon. The flask was putinto a cold bath at −15 to −10° C., then trimethylphosphate (18 ml) wasadded and the reaction mixture stirred. Phosphorous oxychloride (0.865mL, 1.42 gm, 9.28 mmoles, 0.75 eq) was added dropwise from a syringeover a 2 minute period. The reaction was stirred in this cold bath for30 minutes and then placed into a refrigerator at 5° C. for 1-2 days.The reaction was then cooled to −15 to −10° C., and 1 to 6 eq. of waterwas added dropwise over 20 min. The reaction mixture was then placedonto an aminopropyl silica gel column and eluted with a gradient ofethyl acetate: 0.1M acetic acid in methanol: 0.1M acetic acid in waterto give the desired product as its monoacetate salt. ¹H NMR (500 MHz,D₂O) δ 9.43 (d, 2H J=0.6 Hz), 9.21 (dd, 2H, J=6.3, 1.1 Hz), 8.95 (ddd,2H, J=8.1, 1.7, 1.2 Hz), 8.25 (td, 2H, J=7.2, 1.7 Hz), 6.18 (d, 2H,J=5.2 Hz), 4.57 (m, 2H), 4.48 (td, 2H, J=5.1, 2.1 Hz), 4.37 (m, 2H),4.29 (ddd, 2H, J=12.0, 4.8, 2.4 Hz), 4.12 (ddd, 2H, J=12.0, 5.7, 2.7Hz), 1.87 (s, 3H); ¹³C NMR (125 MHz, D₂O) δ 181.40, 165.66, 145.97,142.45, 139.80, 134.00, 128.51, 99.72, 86.92, 77.57, 70.65, 64.64,23.23; ³¹P NMR (200 MHz, D₂O), δ 0.74. (MS(ESI⁺) m/z=571.1 (M⁺).

Preparation of Formula I, n=2

A 50 mL recovery flask was charged with 4.00 g (9.89 mmol) ofnicotinamide riboside trifluoromethanesulfonate and a stir bar. Theflask was purged with argon and capped with a septum. The flask wascooled with an ice bath, then 24 mL of trimethylphosphate was added viasyringe. The mixture was stirred with ice cooling for 5-10 min, then1.45 mL (15.56 mmol) of phosphorus oxychloride was added via syringe.After 3 h, 400 microliters of pyridine was added to the reaction. After5.25 h, 534 microliters of water was added, dropwise over 1 min. Next,3.2 mL of pyridine was added. The suspension was stirred with icecooling for 1.5 h, then stored at 4° C. for 15.5 h.

The reaction was diluted with ethyl acetate until cloudy, then a smallamount of methanol (about 1 mL) was added to give a clear solution. Onehalf of the mixture was loaded onto a 90 g aminopropyl functionalizedsilica gel column (acetate form) that had been pre-equilibrated withethyl acetate. The column was then eluted with a sequence of thefollowing mobile phases: Mobile Phase A—ethyl acetate, Mobile Phase B:0.1M acetic acid in methanol, Mobile Phase C: 0.1M acetic acid in water.The elution sequence was as follows (all ratios are v:v): 1000 mL of A,50:50 A:B, 40:60 A:B, 100% B, 80:20 B:C, 60:40 B:C, 40:60 B:C, and 100%C. The product containing fractions were identified by HPLC MS (ESI⁺,scan mode), with m/z=651 amu as the product mass. The product was mainlyin the 60:40 B:C and 40:60 B:C fractions. The product containingfractions were pooled and concentrated in vacuo to a foam, then taken upin 0.5 mL of water and reconcentrated to a foam. The foam was dissolvedin 3 mL of water, frozen, and lyophilized to give an impure product. Thefoam was re-purified via the same chromatography and lyophilizationsequence to give the desired product as a white solid.

The second half of the crude product solution was then purified via thesame sequence as the first half. This gave a second lot of the productas a white solid. The total yield of the combined lots was 50-500 mg.

1. A compound having the structure:

or a salt thereof.
 2. The compound of claim 1, wherein the salt isformed with a cation selected from H⁺, Li⁺, Na⁺, K⁺, Mg²⁺, and Ca²⁺. 3.The compound of claim 1, wherein the salt is formed with an anionselected from acetate, triflate, halide, trifluoroacetate, formate,H₂PO₄ ⁻, HPO₄ ²⁻, OH⁻, HSO₄ ⁻, SO₄ ²⁻, NO₃ ⁻, HCO₃ ⁻, and CO₃ ²⁻.
 4. Acomposition comprising one or more pharmaceutically-acceptable solidexcipients and one or more compounds having a structure represented byFormula I:

and/or one or more salts thereof, wherein n is
 1. 5. The composition ofclaim 4, wherein the pharmaceutically-acceptable solid excipient isselected from anti-adherent, binder, coating, dye, disintegrant,flavoring agent, glidant, lubricant, preservative, sorbent, sweetener,dispersant, diluent, filler, granulating agent, coating agent, wax,suspending agent, wetting agent, vehicle, and combinations thereof. 6.The composition of claim 4, wherein the composition is in a solid formselected from a tablet, a pill, a capsule, a caplet, a troche, granules,powders, a sachet, dry powder inhalation form, a chewable, a pastille,and a lozenge.
 7. The composition of claim 4, wherein the composition isin the form of a tablet.
 8. The composition of claim 4, wherein thecompound of Formula I is present in the composition in an amount fromabout 0.001% by weight to about 10% by weight.
 9. The composition ofclaim 4, wherein the amount of the compound of Formula I in thecomposition is about 0.25% by weight of the composition.
 10. Thecomposition of claim 4, wherein the pharmaceutically acceptableexcipient is present in an amount of at least about 5% by weight. 11.The composition of claim 4, wherein the pharmaceutically acceptableexcipient is present in an amount of about 30% by weight.
 12. A solidcomposition comprising one or more active pharmaceutical ingredients anda compound having a structure represented by Formula I:

and/or one or more salts thereof, wherein n is
 1. 13. The composition ofclaim 12, wherein the amount of the compound of Formula I relative tothe amount of one or more active pharmaceutical ingredients ranges fromabout 0.001% by weight to less than about 50% by weight.
 14. Thecomposition of claim 12, wherein the amount of the compound of Formula Irelative to the amount of one or more active pharmaceutical ingredientsis from about 0.1% to about 1.5% by weight.
 15. The composition of claim12, wherein the one or more active pharmaceutical ingredients areselected from nicotinic acid (NA), nicotinamide (Nam), nicotinamidemononucleotide (NMN), nicotinamide riboside (NR), nicotinic acidmononucleotide (NaMN), nicotinic acid riboside (NAR), nicotinamideadenine dinucleotide (NAD⁺/NADH), nicotinamide adenine dinucleotidephosphate (NADP), nicotinic acid adenine dinucleotide (NaAD), one ormore compounds of Formula II:

wherein m is 2 or 3, and salts thereof, and combinations thereof. 16.The composition of claim 15, wherein m is
 2. 17. A compound according toclaims 1-3 or a composition according to claims 4-16 for use inincreasing NAD+ levels.
 18. A method of increasing NAD+ levels in asubject in need thereof, said method comprising administering acomposition according to any one of claims 4-17.